Gli aspetti terapeuticiLa steatoepatite:

a sfavorePiero L. AlmasioGastroenterologia & Epatologia,Di.Bi.M.I.S., Università di Palermo

UNIGASTROCOORDINAMENTO NAZIONALE DOCENTI UNIVERSITARI

DI GASTROENTEROLOGIACorso residenziale di formazione per specializzandi in Gastroenterologia

“IL FEGATO COME CENTRALE METABOLICA E I FATTORI DI DANNO OLTRE I VIRUS EPATITICI”San Vincenzo (LI), Riva degli Etruschi

4-6 maggio 2008

NAFLD NASH

NHANES III 23%

Patients undergoing liver biopsy 15-39% 1.2-4.8%

Patients undergoing CT scan 9.7%

Post-mortem analysis (random deaths)

15.6-24% 2.1-2.4%

General population ultrasound screening

16.4-23%

Prevalence of NAFLD and NASH

La epidemia NAFLD/NASH in Italia (stima)

Prevalenza obesità : 18-20% (9-11 milioni)Prevalenza di FL: 43-51% (24-29 milioni)Prevalenza NAFLD: 20-25% (11-14 milioni)

Obesità nella NAFLD: 65-75%Diabete nella NAFLD: 25-30%

Incidenza NAFLD: 400.000 nuovi casi/annoPrevalenza NASH: 10-20% della NAFLD (1.1-1.4

milioni)Incidenza NASH: 40.000-80.000 nuovi casi/annoProgressione della NASH a cirrosi: 10% (110.000-

140.000; 4.000-8.000 all’anno)

Infiammazione (8-20%)

Assenza di fibrosi

Steatosi epatica

Steatosi non infiammatoria

Fibrosi progressiva (10-50%) Tasso di mortalità invariato

Cirrosi (10%) Tasso di mortalità invariato

(NASH)

STORIA NATURALE DELLA NAFLD

Histologic follow up of NASH

Modifyied from Falck-Ytter et al, Semin Liver Dis 2001

Author NFollow up duration,

yrs

Improvedfibrosis,

n

No change in fibrosis,

n

Increasein fibrosis,

n

Powell 13 1-9 1 8 4

Lee 13 1,2-6,9 0 8 5

Bacon 2 4-7 0 1 1

Ratziu 4 2,5-5 0 2 2

Harrison 19 1,4-15,7 4 11 4

Lindor 55 2 12 31 12

TOTAL 106 16% 58% 26%

Survival of NAFLD compared to age-and sex-matched general population

Liver disease was the cause of death in 7/53 patients (13%)

ANGULO et al, Gastroenterology 2005;129:113-121

Factors of NAFLD progressionSurvival of patients with simple steatosis is comparable to the reference populationMost deaths in NAFLD (malignancies, CHD, end-stage liver disease including HCC) are explained by diabetesPredictors of progression: NASH, periportal fibrosis (NPV 100%), insulin resistance, diabetes, increasing BMIALT and AST/ALT ratio do NOT predict

McCullough AJ. N Engl J Med 2006; 355: 2361-3.

Weight Loss+ Physical Exercise

Insulin Sensitivity

Glycemia

Cholesterol and TG

HDL Cholesterol

Blood pressure

Markers of Inflammation

Effect of body weight changes on ALT levels

SUZUKI et al, J Hepatol 2005;43:1060-1066

P<0.0001

NAFLD TreatmentTreatment Cases Type Alternative Duration Outcome Result

Weight Loss or Lifestyle ModificationsEriksson 3 Observational ----- 6-12 mo ALT, Biopsy ++Palmer 39 Observational ----- Unspecified ALTUeno 15 Controlled none 3 mo ALT, Biopsy +++Franzese 38 Observational ----- 6 mo ALT, USKnobler 49 Observational ----- 24 mo ALT +++Kugelmans 16 Observational ----- 3 mo ALT ++Hickman 21 Observational ----- 15 mo ALT,HRQL,Biopsy +++

Insulin-sensitizers- Glitazones

Caldwell 10 Observational ----- 6 mo ALT, Biopsy +++Neuschwander 25 Observational ----- 12 mo ALT, Biopsy +++Promrat 18 Observational ----- 12 mo ALT, Biopsy +++

- MetforminMarchesini 14 Controlled Counseling 4 mo ALT, US +++Coyle (abs) 2 Observational ----- 11 mo ALT, Biopsy +Uygun 36 RCT Diet alone 6 mo ALT, Biopsy ++Nair 15 Observational ----- 12 mo ALT, Biopsy ±Bugianesi 110 RCT Diet/Vitamin E 12 mo ALT, (Biopsy) +++

NAFLD Treatment - Diet & Exercise

25 NASH Patients:15 compliant to lifestyle changes,10 non compliant

Diet: 25 Kcal/kg i.b.w. (20% Protein, 30% Lipid, 50% CHO)Exercise: Walking (3000 to 10,000) steps at 500 stepincrease every 3rd day, then Jogging, 20 min twice a dayDuration: 3 monthsBiopsy: at entry and at 3-monthOutcome:

Anthropometry,Biochemistry,Histology Ueno et al, J Hepatol 1997

Therapeutic effects of diet and exercise in obese patients with NASH

Control pre-treatment

Control post-treatment

Treated-pretreatment

Treated post-treatment

0

30

60

90

Control pre-treatment

Control post-treatment

Treated-pretreatment

Treated post-treatment

ALT

val

ues

Ueno et al., J Hepatol 1997

Therapeutic effects of diet and exercise in obese patients with NASH

Control pre-treatment

Control post-treatment

Treated-pretreatment

Treated post-treatment

0

30

60

90

120

150

180

210

240

Control pre-treatment

Control post-treatment

Treated-pretreatment

Treated post-treatment

chol

este

rol l

evel

s

Ueno et al., J Hepatol 1997

Therapeutic effects of diet and exercise in obese patients with NASH

Control pre-treatment

Control post-treatment

Treated-pretreatment

Treated post-treatment

0

1

2

3

Control pre-treatment

Control post-treatment

Treated-pretreatment

Treated post-treatment

degr

ee o

f ste

atos

is

Ueno et al., J Hepatol 1997

Insulin sensitizer: Metformin

A biquanide, reduces hyperinsulinaemia and improves hepatic insulin resistanceSite of action

in the mitochondriato stimulate pyruvate-kinase, fatty acid beta-oxidation, anaerobic respiration (i.e. lactate production) suppress the expression of lipogenic enzymes

EFFECT OF METFORMIN ON PATIENTS WITH NASH

Entry 1 2 3 40

20

40

60

80

100

Entry 1 2 3 4

DietDiet + Metformin

ALT

val

ues

Marchesini et al., Lancet 2001

months

15 patients with NASH1 year of treatment of metformin (20 mg/kg)Initial 3 months

improvement in ALT/AST and insulinsensitivity

After 3 monthsno further improvement in insulin sensitivity

A gradual rise in AST/ALT back to pre-treatment levels

Nair S, Aliment Pharmacol Ther 2004; 20: 23–8.

METFORMIN THERAPY IN PATIENTS WITH NASH

Controlled trial, randomized 36 patients with NASHA dietary treatment group and a dietary treatment plus metformin, for 6-month A significant decrease in ALT/AST, insulin and C-peptide

PIVENS and TONIC trials by the NIH to clarify long-term benefits

Uygun , Aliment Pharmacol Ther 2004; 19: 537–44

EFFECT OF METFORMIN IN PATIENTS WITH NASH

Regression of MS in 1171 patients:Metformin vs life-style changes

(average FU 3.2 yrs)

ORCHARD et al, Ann Intern Med 2005;142:611-619

P=0.002

Insulin sensitizer: Thiazolidinediones (TZDs)

Peroxisome proliferator activated receptor (PPAR) stimulatorIncrease insulin sensitivity in peripheral adipocytesLower plasma fatty acid concentrations and redistribute intracellular lipidsReduces extracellular matrix deposition and hepatic stellate cells activation in both toxic and cholestatic models of liver fibrosis

Piogitlazone (ACTOS)

18 non-DM with biopsy-proven NASH treated with pioglitazone (30 mg daily) for 48 weeks ALT/AST were in the normal range in 13 patients (72%)ALT levels decreased an average of 50 U/L from baselineHistological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies and fibrosis were also significantly improved from baseline

PROMRAT et al, Hepatology 2004;39:188-196

Effect of pioglitazone of histological parameters in NAFLD

Pre Week 48 PNASH (%) 94 33 <0.01Steatosis 2.5 ± 1.2 1.0 ± 0.9 <0.001Lobular inflammation 3.3 ± 1.0 2.1 ± 1.2 <0.001Mallory bodies 2.2 ± 1.5 1.4 ± 1.5 0.01Fibrosis 2.0 ± 1.1 1.4 ± 1.1 0.04

PROMRAT et al, Hepatology 2004;39:188-196

Pioglitazone and NASH

Promrat et al, Hepatology 2004

n=18

Pioglitazone and NASH

Promrat et al, Hepatology 2004

PioglitazoneBelfort et al performed first placebo-controlled trial investigating Pioglitazone in patients with biopsy-proven NASH and glucose intolerance or type 2 DM

Improvement in hepatic histologic features, except fibrosisDecrease in peripheral and hepatic insulin resistanceDecrease in serum aminotransfereasesIncrease in serum adiponectin

Belfort R, et al. N Engl J Med 2006; 355: 2297-307

Pioglitazone: Results

P=0.04 P<0.001

Belfort R, et al. N Engl J Med 2006; 355: 2297-307

Pioglitazone: Results

Belfort R, et al. N Engl J Med 2006; 355: 2297-307

Study Limitations

Small sample size – only 47 patientsShort study period – 6 monthsShows promise, but need more info

AntioxidantOxidative stress is believed to be a key catalyst in the development of NASHPresume vitamins E and C would help protect against the damaging effects of free radicals in the liver

Effetto del calo ponderale e della somministrazione di vitamina E sulla

elevazione delle ALT

ALT

Kugelmas et al., Hepatology 2003

Effetto della somministrazione di vitamina C e vitamina E in pazienti con NASH

Harrison 2003

fibro

sis

166 NASH pts (122 completed the 2-yr treatment)Stratification for diabetes, obesity, high triglyceridesLiver biopsy at entry and at study end (107 pts)Counseling for overweight ptsUDCA (13-15 mg/kg/d or identical placebo)Changes in liver enzymes from baseline in both groupsImprovement in steatosis, no difference in fibrosis and necroinflammationNo difference between groups

Ursodeoxycholic Acid RCT

Conclusions (1)NAFLD affects a large proportion of the world's population. I.R. and oxidative stress have critical roles in the pathogenesis of NAFLD. Liver biopsy remains the most sensitive and specific means of providing important prognostic information.Simple steatosis may have the best prognosis within the spectrum of NAFLD, but it has the potential to progress to steatohepatitis, fibrosis, and even cirrhosis.No effective medical therapy is currently available for all NAFLD.Weight reduction, when achieved and sustained, may improve the liver disease.

Conclusions (2)

Pharmacologic therapy aimed at the underlying liver disease holds promise.However, questions remain regarding the use of drug therapy and the effect of recommended dietary measures.Liver transplantation is a therapeutic alternative for some p'ts with decompensated, end-stage NAFLD, but NAFLD may recur after liver transplantation.